This is a revised version of the RO1 AR32081-25 which tests the hypothesis that the autoantibody response in humans against desmoglein 1 (Dsg1) and Dsg3 is diverse, ranging from a non-pathogenic and persistent response detected in normal individuals to a frankly pathogenic reaction found in pemphigus vulgaris (PV) and pemphigus foliaceus/fogo selvagem (PF/FS) patients. The skin phenotype in normal and diseased individuals is driven by the epitope specificity of these autoantibodies. It is predicted that phenomena such as epitope cross-reactivity and epitope spreading are feasible in individuals with the appropriate genetic background due to the extensive homology between Dsg1 and Dsg3. This hypothesis explains the prevalence of non-pathogenic and pathogenic anti-Dsgl and anti-Dsg3 autoantibodies in patients and normal individuals, the rare transition of phenotype from PV to PF or PF to PV and the existence of a novel form of "endemic PV" in endemic regions of FS in Brazil. We are interested on determining the fine epitope specificity and the IgG subclass restriction of anti-Dsgl and anti-Dsg3 autoantibodies during the progression of the autoimmune response from normal, pre-clinical and clinical stages of PV and PF/FS. Our studies show that conversion from non-pathogenic anti-Dsgl response (found in normal individuals with anti-EC5 domain) to pathogenic (found in FS patients) is linked to the emergence of population of anti-Ed-2 autoantibodies to this antigen. These projects are facilitated by our unique bank of sera from PV, non-endemic PF, FS and normal donors, which include patients in different stages of disease evolution. We describe exciting novel, unreported studies that stern out of the aims of this grant, e.g. the high frequency and distinctive presence of anti-Dsgl IgM autoantibodies in FS and the presence of anti-E cadherin autoantibodies in PV, PF/FS to name two. We have also characterized several B cell clones from PV, PF and FS and sequenced the IgG V region genes and began to explore the diversity of the autoimmune response in these patients. Similarly, we have also generated human/mouse IgM monoclonal antibodies, which will be further analyzed for V gene diversity. Finally, we will generate human anti-idiotypic antibodies by phage display technology and attempt to block binding of PV or PF/FS autoantibodies to their target epidermal antigens, thus preventing disease.